Asymmetric Samarium-Reformatsky Reaction of Chiral α-Bromoacetyl-2-oxazolidinones with Aldehydes

Article abstract of DOI:10.1021/jo9914317

The samarium(II) iodide mediated asymmetric Reformatsky-type reaction of chiral 3-bromoacetyl-2-oxazolidinones with various aldehydes was studied. A series of chiral 4-substituted 2-oxazolidinones 1-3 and 5,5-disubstituted "SuperQuat" oxazolidinones 4-5 were employed as chiral auxiliaries of the α-bromoacetic acid. The reaction of 1 with various aldehydes gave the α-unbranched β-hydroxy carboximides in good yields with high diastereomeric excess values (up to >99% de). The majority of the reaction product derived from 5,5-diphenyl SuperQuat 5 were highly crystallinity; a single recrystallization yielding a diastereomerically pure product with the other diastereomer not detectable by spectroscopic methods. The absolute configurations of the β-hydroxy carboximides were determined by signs of optical rotations of the corresponding known ethyl esters referring to the literature values. Hydrolytic cleavage of the appended of β-hydroxy moieties from the auxiliary SuperQuats was readily achieved under mild conditions using lithium hydroxide; the corresponding carboxylic acids and the returned SuperQuats were obtained in good yields without any evidence of racemization. The first step of the reaction is the reduction of the α-bromo group to produce the samarium enolate, which adds to an aldehyde. The absolute configuration of the adduct (7i) derive from benzaldehyde was found to be R, with the samarium enolate favoring the transition state predicted from chelation control of the reagent; this is in analogy to the discussion that has been used for the corresponding titanium enolate. The stereochemistry of the reaction may be explained by incorporating the Nerz-Stormes-Thornton chair transition structure model.

Full text of DOI:10.1021/jo9914317

1702
J . Org. Chem. 2000, 65, 1702-1706
Asym m etr ic Sa m a r iu m -Refor m a tsk y Rea ction of Ch ir a l
r-Br om oa cetyl-2-oxa zolid in on es w ith Ald eh yd es
Shin-ichi Fukuzawa,* Hiroshi Matsuzawa, and Shin-ichi Yoshimitsu
Department of Chemistry and Applied Chemistry, Institute of Science and Engineering,
Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551, J apan
Received September 10, 1999
The samarium(II) iodide mediated asymmetric Reformatsky-type reaction of chiral 3-bromoacetyl-
2-oxazolidinones with various aldehydes was studied. A series of chiral 4-substituted 2-oxazolidi-
nones 1-3 and 5,5-disubstituted “SuperQuat” oxazolidinones 4-5 were employed as chiral
auxiliaries of the R-bromoacetic acid. The reaction of 1 with various aldehydes gave the
R-unbranched â-hydroxy carboximides in good yields with high diastereomeric excess values (up
to >99% de). The majority of the reaction product derived from 5,5-diphenyl SuperQuat 5 were
highly crystallinity; a single recrystallization yielding a diastereomerically pure product with the
other diastereomer not detectable by spectroscopic methods. The absolute configurations of the
â-hydroxy carboximides were determined by signs of optical rotations of the corresponding known
ethyl esters referring to the literature values. Hydrolytic cleavage of the appended of â-hydroxy
moieties from the auxiliary SuperQuats was readily achieved under mild conditions using lithium
hydroxide; the corresponding carboxylic acids and the returned SuperQuats were obtained in good
yields without any evidence of racemization. The first step of the reaction is the reduction of the
R-bromo group to produce the samarium enolate, which adds to an aldehyde. The absolute
configuration of the adduct (7i) derive from benzaldehyde was found to be R, with the samarium
enolate favoring the transition state predicted from chelation control of the reagent; this is in analogy
to the discussion that has been used for the corresponding titanium enolate. The stereochemistry
of the reaction may be explained by incorporating the Nerz-Stormes-Thornton chair transition
structure model.
In tr od u ction
few asymmetric Reformatsky reactions are known; in
contrast, the success of the asymmetric aldol reaction (the
product of a Reformatsky reaction) is widely recognized
and furthermore has been extensively studied.3
Samarium(II) iodide is known to be a highly versatile
reagent, and its use in an intramolecular sense in an
asymmetric Reformatsky reaction has already been
reported.4 There are in the literature examples of highly
stereoselective organic reactions that result in enantio-
merically enriched products via the use of samarium(II)
iodide. Furthermore, the use of samarium(II) iodide as a
chelation control element in intra- and intermolecular
1,2- and l,3-asymmetric inductions seems favorable.5,6 We
The Reformatsky reaction was discovered in 1887 and
has historically involved the reaction between zinc and
an R-halo ester generating in situ an organozinc species;
it is this organozinc reagent that reacts with the aldehyde
or ketone resulting in the corresponding â-hydroxy ester.1
â-Hydroxy esters are functional building blocks that have
found many uses in, for example, natural product syn-
thesis, and these are as a consequence highly prized,
valuable intermediates especially if in an enantiomeri-
cally enriched form.
A common problem associated with the traditional
protocol of using zinc dust is the lack of reactivity
associated with this metal for the R-bromoester; conse-
quently, it is often necessary to “activate” zinc via its
amalgam with, for example, copper or mercury. Alterna-
tive methods are available that incorporate inorganic
metals or organometallic reagents; these often circum-
vent the reactivity problems described and as a conse-
quence allow the reaction to proceed in an expedient
manner.2
(2) For examples for metal and metal salts reagents, see the
following. (a) Al: Maruoka, K.; Hashimoto, S.; Kitagawa, Y.; Yama-
moto, H. J . Am. Chem. Soc. 1977, 99, 7705; Bull. Chem. Soc. J pn. 1980,
53, 3301. Matsubara, S.; Tsuboniwa, N.; Morizawa, Y.; Oshima, K.;
Nozaki, H. Bull. Chem. Soc. J pn. 1984, 57, 3242. (b) Ce: Imamoto, T.;
Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.;
Yokoyama, M. J . Org. Chem. 1984, 49, 3904. Fukuzawa, S.; Tsuruta,
T.; Fujinami, T.; Sakai, S. J . Chem. Soc., Perkin Trans. 1 1987, 1473;
Fukuzawa, S.; Hirai, K. J . Chem. Soc., Perkin Trans. 1 1993, 1963. (c)
Cr: Dubois, J . E.; Axiotis, G.; Bertouneque, E. Tetrahedron Lett. 1985,
26, 4371. (d) Sb: Huang, Y. Z.; Cheng, C.; Shen, Y. J . Chem. Soc.,
Perkin Trans. 1 1988, 2855. (e) Sn: Harada, T.; Mukaiyama, T. Chem,
Lett. 1982, 161, 467. (f) Sm Tabuchi, T.; Kawamura, K.; Inanaga, J .;
Yamaguchi, M. Tetrahedron Lett. 1986, 27, 3889. Inanaga, J .; Yokoya-
ma, Y.; Handa, Y.; Yamaguchi, M. Tetrahedron Lett. 1991, 32, 6371.
(3) (a) Guette, M.; Capillon, J .; Guette, J .-P. Tetrahedron, 1973, 29,
3659. (b) Soai, K.; Kawase, Y. Tetrahedron: Asymmetry 1991, 2, 781.
(c) Soai, K.; Oshio, A.; Saito, T. Chem. Commun. 1993, 811. (d) Ito, Y.;
Terashima, S. Tetrahedron 1991, 47, 2821. (e) Kagoshima, H.; Hash-
imoto, Y.; Oguro, D.; Saigo, K. J . Org. Chem. 1998, 63, 691.
(4) Molandar, G. A.; Etter, J . B.; Harring, L. S.; Thorel, P.-J . J . Am.
Chem. Soc. 1991, 113, 8036.
Highly stereocontrolled asymmetric variants of the
Reformatsky reaction are of current interest and an
efficient asymmetric version of the Reformatsky reaction
would be an exceedingly desirable reaction to have in the
armory of the synthetic chemist. Be that as it may, very
* To whom correspondence should be addressed. Phone: 81-(0)3-
3817-1916. Fax: 81-(0)3-3817-1895. E-mail: fukuzawa@chem.chuo-
u.ac.jp.
(1) For reviews, see: (a) Fu¨rstner, A. Synthesis 1989, 571. (b) Erdik,
E. Organozinc Reagents in Organic Synthesis; CRC Press: London,
1996.
(5) For a review of samarium(II) iodide in organic synthesis, see:
Molander, G. A.; Harris, C. H. Chem. Rev. 1996, 96, 307.
10.1021/jo9914317 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/19/2000

Samarium-Reformatsky Reaction of R-Bromoacetyl-2-oxazolidinones
J . Org. Chem., Vol. 65, No. 6, 2000 1703
Sch em e 1
Sch em e 2
and other research groups have reported that ketyl-
alkene coupling reactions are possible with excellent
diastereoselectivities using chiral auxiliaries bond esters,7
acetals,8 and aldehydes.9 In this study on asymmetric
synthesis incorporating samarium(II) iodide, we have
only been interested in intermolecular asymmetric Re-
formatsky reactions.10 We would like to describe in more
detail the research that was undertaken and results
obtained from the use of Evans’ chiral 2-oxazolidinones
and Davies’ 5,5-disubstituted SuperQuat variants. A
possible reaction mechanism is put forward that accounts
for configuration of resulting aldol adducts.
Ta ble 1. Refor m a tsk y-typ e Rea ction of
r-Br om oa cetyl-2-oxa zolid in on es 1-5 w ith Ald eh yd esa
R in
aldehyde
entry BrCH2COXc
product %, yieldb %, dec
1
2
3
4
5
6
7
8
9d
1
2
3
1
1
1
1
1
1
4
4
4
4
5
5
5
5
i-Pr
i-Pr
i-Pr
Et2CH
c-C6H11
t-Bu
n-C7H15
PhCH2CH2
Ph
i-Pr
t-Bu
n-C7H15
Ph
i-Pr
t-Bu
n-C7H15
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
70
7p
7q
92
88
90
95
78
87
81
67
67
64
66
55
87
32
60
42
32
83
80
78
76
84
>99
82
86
64
Resu lts a n d Discu ssion
We initially tried the reaction of pivalaldehyde with
chiral R-bromoacetate derived from chiral sec-alcohols
(Scheme 1).11 Unfortunately, the diastereoselectivity of
the reaction was not satisfactory, giving a low diastere-
omeric excess (up to 50% de). After screening several
chiral auxiliaries for R-bromoacetic acid, we directed our
attention to the use of chiral 2-oxazolidinone auxiliaries
as the stereochemical controlling element in the asym-
metric samarium-Reformatsky reaction.12 We then ex-
amined the stereoselectivity of the Reformatsky-type
reaction of a Evans’ chiral 3-(2-bromoacetyl)-2-oxazoli-
dinone with isobutyraldehyde using a series of three 4S-
substituted auxiliaries 1-3, e.g., isopropyl, phenyl, and
phenylmethyl. The reaction was usually carried out as
follows. To a tetrahydrofuran (THF) solution of samari-
um(II) iodide (2.0 equiv) was simultaneously added the
3-(2-bromoacetyl)-2-oxazolidinone 1-3 (1 equiv) and an
aldehyde (1.2 equiv) at -78 °C. The resulting mixture
was stirred at the same temperature for 0.5 h, during
which time the color of the solution turned from deep
green to yellow-brown. After the usual acidic workup, the
â-hydroxy carboximide 7 was isolated by column chro-
matography (Scheme 2). The diastereomeric excess (%
de) of 7 was determined by GC after trifluoroacetylation
and/or by HPLC in its original form. Almost the same
diastereoselectivities and chemical yields were obtained
in the reaction with each chiral 4-substituted 3-bro-
10
98
11
>96
12
94
13d
14
49
90
15
99
16
70
>99
17d
a
Samarium(II) iodide (2.2 mmol), 1-5 (1.0 mmol), aldehyde (1.0
b
mmol), THF (22 mL): -78 °C, 2 h. Isolated yield. c Determined
d
by GC/MS or HPLC. Benzaldehyde was added after addition of
the R-bromoacetyl-2-oxazolidinone.
moacetyloxazolidinone auxiliary (Table 1, entries 1-3).
For this reason and for ease of analysis by GC/MS, we
chose 1 as the suitable chiral auxiliary for the reaction
with various aldehydes. We turned our attention next to
the effect, i.e., yields and de’s, that different aldehydes
would have on the outcome of the Reformatsky reaction
using 1 (Table 1). The yields of the products were good
to excellent and the de values were high for the straight
chain, branched aliphatic aldehydes and aromatic alde-
hydes. The de value was the highest with the hindered
aldehyde such as pivalaldehyde (entry 6). It is necessary
for the reaction with benzaldehyde that the stepwise
addition of the 3-bromoacetyloxazolidinone first and
benzaldehyde afterward; this obviates the formation of
pinacol as a major product and low yield of the aldol
adduct.
Absolute configurations of the alcoholic carbon in the
â-hydroxy carboximide 7 were determined by converting
them into the corresponding ethyl esters.13 From the sign
of the optical rotations of the â-hydroxy ethyl esters 8 (R
) Ph, i-Pr, n-C7H15), the stereochemistry of the alcoholic
carbon in each compound was revealed to be the R
configuration in 8a (R ) i-Pr) and 8g (R ) Ph) and S
configuration in 8h (R ) n-C7H15) (Table 2).14
(6) (a) Kito, M.; Sakai, T.; Yamada, K.; Matsuda, F.; Shirahama, H.
Synlett 1993, 158. (b) Kawatsura, M.; Matsuda, F.; Shirahama, H. J .
Org. Chem. 1994, 59, 6900. (c) Kawatsura, M.; Hosaka, K.; Matsuda,
F.; Shirahama, H. Synlett 1995, 729. (d) Kawatsura, M.; Dekura, F.;
Shirahama, H.; Matsuda, F. Synlett 1996, 373. (e) Evans, D. A.;
Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112, 6447.
(7) Fukuzawa, S.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J . Am. Chem.
Soc. 1997, 119, 1482.
(8) Molander, G. A.; McWilliams, J . C.; Noll, B. C. J . Am. Chem.
Soc. 1997, 119, 1265.
(9) Taniguchi, N.; Uemura, M. Tetrahedron Lett. 1997, 38, 7199.
(10) For a preliminary communication, see: Fukuzawa, S.; Tat-
suzawa, M.; Hirano, K. Tetrahedron Lett. 1998, 39, 6899.
(11) Chiral 1,1,2-triphenylethanediol has been reported as a useful
chiral auxiliary for aldol reaction. Braun, M.; Graf, S.; Herzog, S. Org.
Synth. 1995, 72, 32; 42.
(12) For a review on chiral oxazolidinones in asymmetric synthe-
sis: Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-
875; Aldrichim. Acta 1997, 30(1), 3.
(13) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127.

1704 J . Org. Chem., Vol. 65, No. 6, 2000
Fukuzawa et al.
Ta ble 2. Tr a n sester ifica tion of â-Hyd r oxy Ca r boxim id e
Ta ble 3. Hyd r olysis of â-Hyd r oxy Su p er Qu a t (7) w ith
(7) w ith Sod iu m Eth oxid e
Lith iu m Hyd r oxid e
%, yield
of 8
entry
7
[R]20
config
D
%, yield
of 9
1
2
3
4
7a ; R ) i-Pr
7f; R ) t-Bu
8a ; 87 +34.30 (c ) 0.708, CHCl3)
8f; 86 +43.48 (c ) 1.48, CHCl3)
R
entry
7
[R]20
config
D
7g; R ) C7H15 8g; 85 +10.43 (c ) 1.24, CHCl3)
S
R
1
2
3
7j; R ) i-Pr
9j; 87 +12.83 (c ) 0.99, MeOH)
R
-
R
7i; R ) Ph
8i; 81 +43.35 (c ) 0.392, CHCl3)
7l; R ) n-C7H15 9l; 81 +14.57 (c ) 1.02, CHCl3)
7m ; R ) Ph
9m ; 85 +29.52 (c ) 0.21, CHCl3)
As described above, the oxazolidinone auxiliaries 1
were revealed to be efficient for the asymmetric sa-
marium-Reformatsky reaction by providing high ste-
reoselectivities and chemical yields. A recent addition to
the oxazolidinone auxiliary family are SuperQuats; these
have been developed by Davies et al. specifically to
overcome the major drawbacks that the Evans oxazoli-
dinones have in the selective removal from the aldol
products and recyclability; the endocyclic cleavage of the
oxazolidinone ring often occurs in hindered carboximides
during nucleophilic hydrolysis to give unwanted prod-
ucts.15 The SuperQuats exhibit highly efficient exocyclic
cleavage properties and furthermore have the overriding
advantage that they are highly crystalline in nature and
in practical terms are identical to the Evans auxiliaries.16
We employed the isopropyl SuperQuat chiral auxiliaries
4 for the samarium-Reformatsky reaction. These results
are also shown in Table 1 (entries 10-13). Though the
yields of the products were lower than those with 1,
stereoselectivities were higher than with 1; the reaction
with isobutyraldehyde and octanal gave 98% and 94%
de, respectively, while the reaction of 1 with these
aldehydes gave 78-82% de. Removal of the SuperQuat
oxazolidinone moiety was easy to carry out by just
treating the â-hydroxy SuperQuat with lithium hydroxide
in THF/H2O for 30 min. The corresponding â-hydroxy
acid 9 and the parent SuperQuat were obtained in high
yields (80-90%) without racemization; the ee value of 9
was comparable with the de value in the parent â-hy-
droxy SuperQuat. The stereochemistry of the alcoholic
carbons in 9 (9j; R ) i-Pr, 9m ; R ) Ph) could also be
determined by the signs of their optical rotations.17 As
both of them exhibited a positive optical rotation, the R
configurations could be assigned in 9j (R ) i-Pr) and in
9m (R ) Ph); the stereochemistry of 9 was in agreement
with that of 8, which was obtained from the 5-unsubsti-
tuted oxazolidinone (Table 3).
Ch a r t 1
auxiliary into our samarium-Reformatsky study; again
for comparison purposes, the (4S)-isopropyl-5,5-diphenyl-
2-oxazolidinone 5 was used. Though the chemical yields
were not satisfactory, the de values were almost the same
as with the SuperQuat 4 (Table 1, entries 14-17), the
5,5-diphenyl SuperQuat 5 has an advantage that conveys
a high degree of crystallinity to the products, which are
easy to purify by a single recrystallization to give the
diastereomerically pure compounds.
The first step of the samarium-Reformatsky reaction
should involve the reduction of the R-bromoacetyl group
of 1 to give the samarium imide enolate 10, which
nucleophilically attacks the aldehyde (Chart 1). The
samarium atom would then play an important role in the
transition state of the reaction for high diastereoselec-
tivity (vide infra). Chiral oxazolidinone auxiliaries are
often employed for the asymmetric aldol reaction with
metal (Li,19 B,13 Zn,3d Ti,19 Ge3e) enolates of 3-propionyl-
oxazolidinone 11, where a high degree of diastereoselec-
tivity can be achieved (over 99% de).3d-e,13 On the other
hand, the aldol reaction with the metal enolates of the
acetyloxazolidinone 12 afforded low or no diastereose-
lectivity. For example, Evans et al. reported that the
reaction of a boron enolate of 12 with isobutyraldehyde
gives a mixture of diastereomers in the ratio of 52:48.13
Thus, the R-methyl group seems to be critical for achiev-
ing a highly diastereoselective aldol reaction, including
Reformatsky reaction. The R-methylthio-substituted acetyl-
oxazolidinone may be used for the stereoselective prepa-
ration of an R-unbranched â-hydroxy carboximide after
reductive removal of the methylthio group.13 The sa-
marium imide enolate is superior to the other metal
imide enolate for directly preparing R-unbranched â-hy-
droxy acids or esters without any modification of the
organic molecule.19
A more sterically crowded derivative of the original
gem-dimethyl SuperQuat auxiliary has been developed,
namely the gem-5,5-diphenyl-2-oxazolidinone (5,5-di-
phenyl SuperQuat).18 We sought to incorporate this
(14) For literature values of optical rotations: (S)-(8a ; R ) i-Pr),
[R]D ) -14.3 (c ) 0.3, MeOH), Sugiyama, T.; Yoshikawa, M.; Yoneda,
T.; Tai, A. Bull. Chem. Soc. J pn. 1990, 63, 1089. (R)-(8g; R ) C7H15),
[R]D ) -10.0 (c ) 1.20, CHCl3), Basile, T.; Tagliavini, E.; Trombini,
C.; Umani-Ronchi, A. Synthesis 1990, 305. (R)-(8i; R ) Ph), [R]D
)
(18) Gibson, C. L.; Gillon, K.; Cook, S. Tetrahedron Lett. 1998. 39.
6733.
+43.1 (c ) 3.11, CHCl3), Soai, K.; Yamanoi, T.; Hikima, H.; Oyamada,
H. Chem. Commun. 1985, 138.
(19) For examples for successful asymmetric synthesis of R-un-
branched â-hydroxy acids or esters, see: (a) Dongala, E. B.; Dull, D.
L.; Miioskowski, C.; Soladie, G. Tetrahedron Lett. 1973, 4983. (b)
Mukaiyama, T.; Iwasawa, N.; Stevens, R. W.; Haga, T. Tetrahedron
1984, 40, 1381. (c) Nagao, Y.; Hagiwara, Y.; Kumagai, Y.; Ochiai, M.;
Inoue, T.; Hashimoto, K.; Fujita, E. J . Org. Chem. 1986, 51, 2393. (d)
Duthaler, R. O.; Hafner, M.; Riediker. Pure Appl. Chem. 1990, 62, 631.
(e) Cooke, J . W. B.; Davies, S. G.; Naylor, A. Tetrahedron, 1993, 49,
7955 and ref 10.
(15) Davies, S. G.; Doisneau, G. J .-M.; Prodger, J . C.; Sanganee, H.
J . Tetrahedron Lett. 1994, 35, 2369.
(16) (a) Davies, S. G.; Sanganee, H. J . Tetrahedron: Asymmetry
1995, 6, 671. (b) Bull, S. D.; Davies, S. G.; J ones, S.; Polywka, M. E.
C.; Prasad, R. S.; Sanganee, H. J . Synlett 1998, 519.
(17) For literature values of optical rotations: (S)-(9j; R ) i-Pr), [R]D
) -42.1 (c ) 1.8, CHCl3); (S)-(9m ; R ) Ph), [R]D ) -17.1 (c ) 4.1,
EtOH).13

Samarium-Reformatsky Reaction of R-Bromoacetyl-2-oxazolidinones
J . Org. Chem., Vol. 65, No. 6, 2000 1705
4S-3-(2-b r om oa cet yl)-4-(1-m et h ylet h yl)-2-oxa zolid i-
n on e (1). The following provides the typical experimental
procedure for the preparation of the chiral 3-(2-bromoacetyl)-
2-oxazolidinones. In a two-neck round-bottom flask containing
a magnetic stirring bar were charged 4S-(1-methylethyl)-2-
oxazolidinone (6.50 g, 50 mmol) and dry THF (200 mL) under
a slight pressure of nitrogen. The flask was cooled in a dry
ice-methanol bath (-78 °C), and a hexane solution of n-BuLi
(1.6 M, 35 mL, 55 mmol) was then added using a syringe
through the septum with magnetic stirring. After 30 min,
bromoacetyl chloride (8.00 g, 51 mmol) was slowly added to
the mixture at the same temperature over a period of 20 min.
When the addition was completed, the dry ice bath was
removed, and the mixture was allowed to warm to room
temperature and stirred for an additional 1 h. The reaction
was quenched with saturated aqueous potassium hydrogen
phosphate (50 mL), and the solution was then extracted with
three 50 mL portions of diethyl ether. The combined extracts
were dried over MgSO4, and the solvent was removed on a
rotary evaporator leaving an orange liquid. The crude product
was purified by column chromatography on silica gel with
hexane/ethyl acetate ) 3:1 as the eluent to give a pale yellow
Sch em e 3
Nerz-Stormes and Thornton reported that the reaction
of the lithium and titanium enolates of 12 with benzal-
dehyde mainly gives the S (77% de) and R isomers (50%
de), respectively.20 The stereochemistry of the reaction
with lithium enolate is determined by a nonchelated
transition structure not coordinated to the oxazolidinone
carbonyl, while the stereochemistry of the titanium
enolate is predominated by chelation control, thus coor-
dinated to the oxazolidinone carbonyl. We confirmed the
stereochemistry of the samarium-Reformatsky adduct
with benzaldehyde (7i); it is R, like the aldol adduct with
a titanium enolate. It may be concluded that the sa-
marium enolate strongly favors the adduct predicted by
chelation control analogous to a titanium enolate.20 Thus,
the stereochemistry of the reaction may be explained by
the Nerz-Stormes-Thornton chair transition structure
model as shown in Scheme 3.21 In the chelated transition
state, samarium enolate disfavors a si face the attack on
aldehyde because the isopropyl group is oriented in a
sterically hindered environment. The samarium enolate
then favors the less hindered re face attack on the
aldehyde, preferably leading to the R alcohol isomer.
solid (10.0 g, 40 mmol, 80% yield): pale yellow solid; mp 45-
1
47 °C; [R]20 ) +66.35 (c ) 1.037, CHCl3); H NMR (CDCl3,-
D
400 MHz) δ 0.91 (d, 3H, J ) 7.0 Hz), 0.94 (d, 3H, J ) 7.0 Hz),
2.42 (sept d, 1H, J ) 3.2, 7.0 Hz), 4.28 (dd, 1H, J ) 3.2, 9.0
Hz), 4.36 (dd, 1H, J ) 8.3, 9.0 Hz), 4.46 (m, 1H), 4.42 (d, 1H,
J ) 12.1 Hz), 4.60 (d, 1H, J ) 12.1 Hz); 13C NMR (CDCl3) δ
14.4, 14.5, 18.6, 27.8, 58.4, 63.9, 153.3, 165.7; IR (KBr) 1776,
1695 (νCdO). Anal. Calcd for C8H12BrNO3: C, 38.42; H, 4.84;
N, 5.60. Found: C, 38.16; H, 4.79; N, 5.42.
Sa m a r iu m (II) Iod id e Med ia ted Refor m a tsk y-Typ e Re-
a ction . All reactions were carried out in a nitrogen atmo-
sphere using a Schlenk tube with standard techniques for air-
sensitive materials. The following description provides a
typical experimental procedure for the Reformatsky-type reac-
tion of a chiral 3-bromoacetyl-2-oxazolidinone with aldehydes.
Under the nitrogen atmosphere, samarium powder (Nippon
Yttrium Co., Ltd., 99.9%) (350 mg, 2.2 mmol) was placed in a
50-mL Schlenk tube equipped with a magnetic stirring bar. A
dry THF (20 mL) solution of diiodomethane (540 mg, 2.0 mmol)
was added using a syringe through a septum. The mixture
was stirred for 2 h at room temperature, and samarium(II)
iodide solution was obtained as a deep green solution. The
Schlenk tube was cooled in a dry ice-methanol bath, and a
mixture of isobutyraldehyde (80 mg, 1.0 mmol) and 1 (250 mg,
1.0 mmol) in dry THF (2 mL) was slowly dropwise injected
over a period of 5 min. The resulting solution was stirred at
-78 °C for 0.5 h, during which time the deep green color of
the solution faded. The solution was hydrolyzed with 25 mL
of 0.1 mol/L hydrochloric acid, and the aqueous phase was
extracted with three 20 mL portions of diethyl ether. The
organic phase was washed with aqueous sodium thiosulfate
to remove liberated iodine and brine and then dried over
magnesium sulfate. The solvent was removed under reduced
pressure, and the yellow residue was subjected to preparative
TLC on silica gel (hexane/ethyl acetate ) 2:1 as eluent) to
afford a mixture of the diastereomers of 4S-3-[3-hydroxy-4-
methylpentanoyl]-4-(1-methylethyl)-2-oxazolidinone (7a ) as a
colorless liquid (223 mg, 0.92 mmol, 92% yield). The diaster-
eomeric excess of 83% the product was determined by GC/MS
analysis after trifluoroacetylation with trifluoroacetic anhy-
dride. The absolute configuration of the 3-alcoholic carbon was
determined after transesterification leading to the â-hydroxy
ester (vide infra): [R]20D ) +95.07 (c ) 0.588, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 0.82 (d, 3H, J ) 7.0 Hz), 0.86 (d, 3H, J )
7.0 Hz), 0.89 (d, 3H, J ) 6.9 Hz), 0.91 (d, 3H, J ) 6.9 Hz),
1.6-1.7 (m, 1H), 2.2-2.4 (m, 1H), 2.90 (br s, 1H), 2.94 (dd,
1H, J ) 10.0, 17.1 Hz), 3.09 (dd, 1H, J ) 2.5, 16.8 Hz), 3.82
(m, 1H), 4.23 (dd, 1H, J ) 3.0, 9.0 Hz), 4.28 (dd, 1H, J ) 8.1,
9.0 Hz), 4.45 (ddd, 1H, J ) 3.0, 3.9, 8.1 Hz); 13C NMR (CDCl3)
δ 14.4, 17.6, 28.2, 39.6, 46.1, 58.1, 63.2, 68.9, 153.9, 172.9; IR
(CCl4) 3567 (νOH), 1791, 1691 (νCdO) cm-1. Anal. Calcd for
Exp er im en ta l Section
Gen er a l Met h od s. 1H (400 MHz) and 13C NMR spectra
were recorded in CDCl3, and the chemical shifts are reported
in δ units downfield from tetramethylsilane used as the
internal standard. GC/MS analyses were carried out using a
capillary column (DB-5-30N-STD, J &W Scientific, 0.25 mm,
30 m) and helium as the carrier gas. HPLC analyses were
performed on a Daicel Chiralcel OD and OB columns (0.46 mm,
25 cm) eluting with 2-propanol/n-hexane (1/9-1/100) or a ODS
(Kanto Chemicals Ltd., Mightysil RP-18) column. Elemental
analyses were carried out in the Microanalytical Laboratory
at Chuo University. Column chromatography was performed
using Merck silica gel 60.
Ma ter ia ls. THF was freshly distilled from sodium ben-
zophenone ketyl. 4S-(1-methylethyl)-, 4R-(1-methylethyl)-, 4S-
(phenyl)-, and 4S-(phenylmethyl)-2-oxazolidinone were pur-
chased from Aldrich Co., Inc., or prepared by the reaction of
the corresponding chiral amino alcohols and diethyl carbonate.
Modified chiral oxazolidinones, i.e., 4S-(1-methylethyl)-5,5-
dimethyl-2-oxazolidinone (isopropyl SuperQuat) and 4S-(1-
methylethyl)-5,5-diphenyl SuperQuat, were prepared by the
reported method.16,18 All of the aldehydes and ketones are
commercially available and purified by distillation under
reduced pressure before use.
(20) Nerz-Stormes, M.; Thornton, E. R. J . Org. Chem. 1991, 56, 2489.
(21) Addition of more than 4 equiv of hexamethylphosphoric amide
to samarium(II) iodide remarkably decreased the diastereoselectivity
(59% de) in 7a , suggesting the chelation control should be involved in
the high diastereoselectivity.
C
12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.47; H,
8.68; N, 5.59.

1706 J . Org. Chem., Vol. 65, No. 6, 2000
Fukuzawa et al.
Tr a n sester ifica tion of th e â-Hyd r oxy Ca r boxim id e
w ith Sod iu m Eth oxid e. In a two-neck round-bottom flask
containing a magnetic stirring bar were charged a diastereo-
meric mixture of 7a (120 mg, 0.50 mmol, 83% de) and
anhydrous ethanol (5 mL). The flask was then cooled in an
ice bath, and an ethanolic (1 mL) solution of sodium ethoxide
(70 mg, 1.0 mmol) was added. The resulting mixture was
stirred at 0 °C, and the reaction was monitored by TLC. After
20 min, the reaction mixture was quenched with aqueous
ammonium chloride and extracted with three 15 mL portions
of diethyl ether. The combined extracts were dried over
magnesium sulfate, and the solvent was removed on a rotary
evaporator to give a pale yellow residue. The residue was
subjected to preparative TLC (silica gel, hexane/ethyl acetate
) 4:1): Rf ) 0.3, ethyl 3R-hydroxy-4-methylpentanoate (8a ),
72 mg, 0.45 mmol, 90% yield; Rf ) 0.1, 4S-(1-methylethyl)-2-
was then cooled in an ice bath, and an aqueous (3 mL) solution
of lithium hydroxide (50 mg, 2.0 mmol) was added. The
resulting mixture was stirred at 0 °C, and the reaction was
monitored by TLC. After 30 min, the reaction mixture was
quenched with aqueous sodium bicarbonate and extracted with
three 20 mL portions of diethyl ether: the SuperQuat was
extracted into organic layer and sequential procedure, drying
(MgSO4), filtration, and evaporation of solvent, gave 149 mg
(95%) of the crude SuperQuat. Aqueous layer was then
acidified by concentrated hydrochloric acid and extracted with
three 20 mL portions of diethyl ether. The combined extracts
were dried over magnesium sulfate, and the solvent was
removed on a rotary evaporator to give a pale yellow liquid.
3R-hydroxy-4-methylpentanoic acid (9m ), 141 mg, 0.85 mmol,
85% yield: [R]20D ) +29.52(c ) 0.21, CHCl3); 1H NMR (CDCl3,-
400 MHz) δ 2.77 (dd, 1H, J ) 3.8, 16.6 Hz), 2.85 (dd, 1H, J )
9.3, 16.6 Hz), 5.17 (dd, 1H, J ) 3.6, 9.3 Hz), 7.5-7.7 (m, 5H).
oxazolidinone, 116 mg, 0.90 mmol, 90% recovered): colorless
1
liquid; [R]20 ) +32.34 (c ) 0.708, CHCl3); H NMR (CDCl3,
D
Ack n ow led gm en t. This work was supported by
Sumitomo Foundation Ltd. and the grant of Institute
of Science and Engineering, Chuo University. We wish
to thank Professor Stephen G. Davies, The Dyson
Perrins Laboratory, Oxford University, for his useful
comments on this manuscript.
400 MHz) δ 0.92 (d, 3H, J ) 6.9 Hz), 0.96 (d, 3H, J ) 6.7 Hz),
1.28 (t, 3H, J ) 7.1 Hz), 1.73 (oct, 1H, J ) 6.6 Hz), 2.42 (dd,
1H, J ) 9.5, 16.4 Hz), 2.50 (dd, 1H, J ) 2.7, 16.3 Hz), 3.78-
3.81 (ddd, 1H, J ) 2.9, 6.4, 9.5 Hz), 4.18 (q, 2H, J ) 7.0 Hz);
13C NMR (CDCl3) δ 14.1, 17.7, 18.3, 33.1, 38.4, 60.6, 72.7, 173.0.
GC analysis of trifluoroacetylated ethyl 3R-hydroxy-4-methyl
pentanoate using chiral capillary column (Astec, Chiraldex
G-TA, 30 m) revealed that the ee value (83%) was consistent
with the de value of the parent â-hydroxy carboximide.
Hyd r olysis of th e â-Hyd r oxy Su p er Qu a t w ith Lith iu m
Hyd r oxid e. In a two-neck round-bottom flask containing a
magnetic stirring bar were charged a diastereomeric mixture
of 7m (305 mg, 1.0 mmol, 49% de) and THF (15 mL). The flask
Su p p or tin g In for m a tion Ava ila ble: Spectral and ana-
lytical data of compounds 2-5 and 7b-q and copies of 1H and
13C NMR spectra of 1-5 and 7a -q. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9914317